The present invention relates to the process of diagnosing malignant tumors and, in particular, it concerns a method and system for screening patients with gynecologic tumors so as to determine whether such tumors are likely to be benign or malignant.
It is known that ovarian malignancies represent the primary cause of mortality due to gynecological cancer (D. W. Cramer, "Epidemiologic and statistical aspects of gynecologic oncology," in: R. C. Knapp and R. S. Berkowitz, eds. Gynecologic Oncology. New York: McMillian, 1986). As tumors of this nature may remain quiescent for long periods of time, patients with ovarian malignancies are often diagnosed late in the course of their disease (S. Salem, "What is Doppler's role in adnexal masses?" Diagnostic Imaging Europe, December 1996: F19-F26). The initial diagnosis of an ovarian or other pelvic mass (by which is meant any tumor manifesting in the area of the female reproductive system) is usually rapidly confirmed by a gynecological ultrasound examination. The question then arises as to whether or not the tumor is malignant, the implication of which being that immediate and extensive surgery and chemotherapy may be necessary. Immediate surgical biopsy of all pelvic tumors at the time of initial diagnosis so as to rule out malignancy would be unnecessarily invasive in most cases, however as the majority of such tumors are, in fact, benign. Effort has therefore been directed not only at the early diagnosis of pelvic cancer, but also at the development of non-invasive screening techniques to identify which pelvic tumors are possibly malignant and warrant immediate surgical biopsy. As diagnostic gynecologic ultrasound is universally indicated for all patients with suspected pelvic malignancy, it is the ideal non-invasive diagnostic modality for such screening, which could then be performed at the time of initial diagnosis. Unfortunately, although ultrasound is highly accurate in detecting the presence of pelvic masses, the ultrasound appearance of such masses is often non-specific with regard to the likelihood of malignancy. Ancillary ultrasound indicators of malignancy in pelvic tumors have thus been investigated, in an attempt to improve the specificity of ultrasound as a screening technique.
Indirect evidence of malignancy may be inferred from the nature of blood-flow through malignant tissue. Because malignant tissue grows in a rapid and haphazard fashion, angiogenesis within such tumors tends to be abnormal (J. Folkman, "Tumor Angiogenesis," in: Advances in Cancer Research, 1985, vol. 43:175-203; J. Folkman, K. Watson, D. Ingber, and D. Hanahan, "Induction of angiogenesis during the transition from hyperplasia to neoplasia," Nature. 1989;339:58-61), resulting in blood vessels and capillaries which are more dilated than usual. The vasculature of malignant tissue thus presents less impedance (by which is meant vascular resistance) to blood-flow than does the normal capillary bed found in a benign tumor. Lower vascular impedance may result in a higher diastolic flow velocity (R. S. Thompson, B. J. Trudinger and C. M. Cook. "Doppler ultrasound waveform indices: A/B ratio, pulsatility index and Pourcelot ratio," Br J Obstet Gynaecol. 1988;95:581-8. M. Kawai, T. Kano, F. Kikkawi, O. Maeda, H. Oguchi, and Y. Tomada, "Transvaginal Doppler ultrasound with color flow imaging in the diagnosis of ovarian cancer," Obstet Gynecol. 1992;79:163-7. A. Kurjak, H. Schulman, A. Sosic, I. Zalud, and H. Shalan, "Transvaginal ultrasound, color flow and Doppler waveform of the postmenopausal adnexal mass," Obstet Gynecol. 1992;80:917-21. R. Tepper, L. Lerner-Geva, M. Altaras, S. Goldberger, G. Ben-Baruch, S. Markov, I. Cohen, and Y. Beyth, "Transvaginal color flow imaging in the diagnosis of ovarian tumors," J Ultrasound Med.1995; 14:731-734. Z. Weiner, I. Thaler, D. Beck, S. Rottem, M. Deutsch, and J. M. Brandes, "Differentiating malignant from benign ovarian tumors with transvaginal color flow imaging," Obstet Gynecol. 1992;79:159-62.). Doppler techniques have therefore been used to evaluate the nature of diastolic flow within pelvic tumors as a means of inferring the vascular impedance, and thus the likelihood of malignancy, of such tumors. To date, flow impedance has been inferred from Doppler flow tracings by calculating either the pulsatility index (PI) or the resistive index (RI). The PI is derived from the following formula: peak systolic velocity minus end diastolic velocity divided by the mean velocity. The RI is peak systolic velocity minus end diastolic velocity divided by the peak systolic velocity.
The utility of both the PI and the RI as indicators of ovarian malignancy has been extensively investigated (R. K. Goswami, G. Williams, and P. C. Stepto, "Decreased uterine perfusion: a cause of infertility," Hum Reprod. 1988;3:955-9. K. Shimamoto, S. Sukuma, T. Ishigaki, and N. Makino, "Intratumoral blood flow: evaluation with color Doppler echography," Radiology.1987;165:683-5. R. Tepper, M. Altaras, S. Goldberger, Y. Zalel, M. Cordoba, and Y. Beyth, "Color Doppler ultrasonographic findings in low and high grade endometrial stromal sarcomas," J Ultrasound Med. 1994; 13:817-819. R. Tepper, L. Lerner-Geva, M. Altaras, S. Goldberger, G. Ben-Baruch, S. Markov, I. Cohen, and Y. Beyth, "Transvaginal color flow imaging in the diagnosis of ovarian tumors," J Ultrasound Med. 1995; 14:731-734. R. Tepper, Y. Zalel, M. Altaras, G. Ben-Baruch, and Y. Beyth, "Transvaginal color Doppler ultrasound in the assessment of invasive cervical carcinoma," Gynecologic Oncology. 1996;60:26-29.). Although initial reports were encouraging, more extensive reviews have shown that both the PI and the RI are, in fact, unreliable predictors of the presence of malignancy at biopsy (T. Bourne, S. Campbell, C. Steer, M. I. Whitehead, and W. P. Collins, "Transvaginal color flow imaging: a possible new screening technique for ovarian cancer," Br Med J. 1989;299:1367-70. B. Bromley, H. Goodman, and B. Banacerraf, "Comparison between sonographic morphology and Doppler waveform for the diagnosis of ovarian malignancy," Obstet Gynecol. 1994;83:434-7. R. Tepper, L. Lerner-Geva, M. Altaras, S. Goldberger, G. Ben-Baruch, S. Markov, I. Cohen, and Y. Beyth. "Transvaginal color flow imaging in the diagnosis of ovarian tumors," J Ultrasound Med. 1995; 14:731-734. L. Valentin, P. Sladkevicius, and K. Marsal, "Limited contribution of Doppler velocimetry to differential diagnosis of extrauterine pelvic tumors," Obstet Gynecol.1994;83:425-33. U. M. Hamper, S. Sheth, F. M. Abbas, N. B. Rosenshein, D. Aronson, and R. J. Kurman, "Transvaginal color Doppler sonography of adnexal masses: differences in blood flow impedance in benign and malignant lesions," AJR 1993;160:1225-8. A. Tekay and P. Joupilla, "Validity of pulsatility and resistance indices in classification of adnexal tumors with transvaginal color Doppler ultrasound," Ultrasound Obstet Gynecol. 1992;2:338-44.). As there are no other effective screening tests available, many patients with suspected ovarian or other pelvic malignancy still undergo unnecessary surgical biopsy.
There is therefore a need for a new, reliable, non-invasive method for assessing the likelihood of malignancy of pelvic tumors.